Mechanisms of Endocytosis in Adrenal Chromaffin Cells.

肾上腺嗜铬细胞的内吞作用机制。

基本信息

  • 批准号:
    0344768
  • 负责人:
  • 金额:
    $ 60.35万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
    Continuing Grant
  • 财政年份:
    2004
  • 资助国家:
    美国
  • 起止时间:
    2004-07-01 至 2009-06-30
  • 项目状态:
    已结题

项目摘要

Mechanisms of Endocytosis in Adrenal Chromaffin CellsCorey B. SmithCase Western Reserve UniversityStress is a physiological response to a hostile environment. Stress causes chromaffin cells of the adrenal gland to increase their release of chemical transmitters, including adrenaline, into the blood stream. This release is achieved by fusion of transmitter containing packets, called secretory granules, with the inside cell surface, causing their contents to be expelled from the cell. Under normal conditions, chromaffin cells release low levels of adrenaline and set the organism in a 'breed and feed' state of energy storage by directing blood flow to the internal organs, focusing the eye on nearby objects and increasing insulin release from the pancreas. With stress, chromaffin cells release elevated levels of adrenaline, contributing to the 'fight or flight' response. In this state, the elevated adrenaline diverts blood flow to skeletal muscle, focuses they eye on distant objects and increases blood sugar levels. In addition, stress-activation causes chromaffin cells to release analgesic compounds, termed enkephalins. Together these signaling molecules place the organism into a state for escape or defense. Thus, regulated transmitter release from chromaffin cells plays a critical role in determining the physiological and metabolic status of an organism. It is the overall goal of this laboratory to provide a fundamental understanding of the chromaffin cell as a primary contributor to the 'breed and feed' as well as the 'fight or flight' state. This proposal focuses on the mechanisms utilized by chromaffin cells for transmitter release under basal versus stress activation.Sustained transmitter release requires the recycling of the transmitter-containing secretory granules. Without recycling the cell would soon exhaust its supply. Specialized granule components are retrieved from the cell surface and refilled with transmitter molecules for re-use. It was assumed that this recycling occurred by the same mechanism under all conditions. However, it was recently demonstrated that differences in recycling processes exist under basal versus stress-activation. This proposal outlines a series of experiments designed to test signature events that delineate recycling mechanisms under conditions of basal versus stress activation in mouse adrenal chromaffin cells. It provides experiments that will test the degree of granule fusion and collapse during transmitter release and the degree to which the granule and cell surface components mix, thus defining the complexity of the recycling process required prior to re-generation of viable secretory granules. It will also determine the role of key molecules involved in the recycling mechanism, thus defining points of potential regulation for the re-generation of secretory granules. Techniques employed in these experiments include electrophysiological measures of the surface area of single cells, electrochemical determination of the amount of transmitter released, quantitative fluorescence imaging of cell surface components and molecular disruption of the recycling mechanism. Thus a fundamental description of the mechanisms utilized by adrenal chromaffin cells for the sustained release of adrenaline and enkephalin during the normal 'breed and feed' as well as the 'fight or flight' stress-activated state will be provided.
肾上腺嗜铬细胞的内吞机制。SmithCase Western Reserve UniversityStress是一种对恶劣环境的生理反应。压力会导致肾上腺嗜铬细胞增加化学递质的释放,包括肾上腺素,进入血液。这种释放是通过含有递质的包(称为分泌颗粒)与细胞内表面融合而实现的,导致其内容物从细胞中排出。在正常情况下,嗜铬细胞释放低水平的肾上腺素,并通过将血流引导到内部器官,将眼睛集中在附近的物体上,并增加胰腺的胰岛素释放,使生物体处于“繁殖和喂养”的能量储存状态。在压力下,嗜铬细胞会释放出高水平的肾上腺素,促成“战斗或逃跑”的反应。在这种状态下,升高的肾上腺素将血流转移到骨骼肌,将目光集中在远处的物体上,并增加血糖水平。此外,应激激活导致嗜铬细胞释放镇痛化合物,称为脑啡肽。这些信号分子一起将生物体置于逃避或防御的状态。因此,从嗜铬细胞释放的调节性递质在决定生物体的生理和代谢状态中起着关键作用。本实验室的总体目标是提供对嗜铬细胞作为“繁殖和喂养”以及“战斗或逃跑”状态的主要贡献者的基本理解。本研究的重点是探讨嗜铬细胞在基础激活和应激激活下释放递质的机制。持续释放递质需要含有递质的分泌颗粒的再循环。如果不进行回收,电池很快就会耗尽其供应。从细胞表面取回专门的颗粒成分,并重新填充递质分子以供重复使用。据推测,这种再循环在所有条件下通过相同的机制发生。然而,最近的研究表明,在基础与应力激活下存在回收过程的差异。该提案概述了一系列旨在测试签名事件的实验,这些事件描绘了小鼠肾上腺嗜铬细胞在基础与应激激活条件下的回收机制。它提供了实验,将测试在发射器释放过程中的颗粒融合和崩溃的程度,以及颗粒和细胞表面成分混合的程度,从而定义了再生活性分泌颗粒之前所需的回收过程的复杂性。它还将确定参与再循环机制的关键分子的作用,从而确定分泌颗粒再生的潜在调节点。这些实验中采用的技术包括单细胞表面积的电生理学测量、释放的发射器量的电化学测定、细胞表面组分的定量荧光成像和再循环机制的分子破坏。因此,肾上腺嗜铬细胞的持续释放肾上腺素和脑啡肽在正常的“饲养和饲料”以及“战斗或飞行”的应激激活状态的机制的基本描述将提供。

项目成果

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Corey Smith其他文献

Immune-based therapeutic approaches to virus-associated cancers.
基于免疫的病毒相关癌症治疗方法。
  • DOI:
    10.1016/j.coviro.2018.08.010
  • 发表时间:
    2018
  • 期刊:
  • 影响因子:
    5.9
  • 作者:
    Corey Smith;R. Khanna
  • 通讯作者:
    R. Khanna
Coinfection with Human Cytomegalovirus Genetic Variants in Transplant Recipients and Its Impact on Antiviral T Cell Immune Reconstitution
移植受者中人巨细胞病毒遗传变异的合并感染及其对抗病毒 T 细胞免疫重建的影响
  • DOI:
    10.1128/jvi.00297-16
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    5.4
  • 作者:
    Corey Smith;R. Brennan;Siok;M. Smyth;S. Burrows;John J Miles;G. Hill;R. Khanna
  • 通讯作者:
    R. Khanna
Regulation of protein translation through mRNA structure influences MHC class I loading and T cell recognition
通过 mRNA 结构调节蛋白质翻译影响 MHC I 类负载和 T 细胞识别
Novel autologous T-cell therapy for drug-resistant cytomegalovirus disease after lung transplantation.
肺移植后耐药巨细胞病毒病的新型自体 T 细胞疗法。
Repurposing Licensed Drugs with Activity Against Epstein–Barr Virus for Treatment of Multiple Sclerosis: A Systematic Approach
  • DOI:
    10.1007/s40263-024-01153-5
  • 发表时间:
    2025-01-10
  • 期刊:
  • 影响因子:
    7.400
  • 作者:
    Vivien Li;Fiona C. McKay;David C. Tscharke;Corey Smith;Rajiv Khanna;Jeannette Lechner-Scott;William D. Rawlinson;Andrew R. Lloyd;Bruce V. Taylor;Julia M. Morahan;Lawrence Steinman;Gavin Giovannoni;Amit Bar-Or;Michael Levy;Natalia Drosu;Andrew Potter;Nigel Caswell;Lynne Smith;Erin C. Brady;Bruce Frost;Suzanne Hodgkinson;Todd A. Hardy;Simon A. Broadley
  • 通讯作者:
    Simon A. Broadley

Corey Smith的其他文献

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{{ truncateString('Corey Smith', 18)}}的其他基金

Electrical and Optical Monitoring of Facilitation Mechanisms in Chromaffin Cells
嗜铬细胞中促进机制的电学和光学监测
  • 批准号:
    0196136
  • 财政年份:
    2001
  • 资助金额:
    $ 60.35万
  • 项目类别:
    Continuing Grant
Electrical and Optical Monitoring of Facilitation Mechanisms in Chromaffin Cells
嗜铬细胞中促进机制的电学和光学监测
  • 批准号:
    9985559
  • 财政年份:
    2000
  • 资助金额:
    $ 60.35万
  • 项目类别:
    Continuing Grant

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    2023
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    23K08013
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    2023
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